NKX6-2 Disease in Two Unrelated Patients with Early-Onset Spastic Quadriplegia and Diffuse Hypomyelinating Leukodystrophy

Recently, biallelic variants in NKX6-2 have been reported to cause central nervous system hypomyelination. Clinical presentation of previously reported patients included two distinct phenotypes: a neonatal-onset with severe presentation, and a milder childhood-onset form. To date, there have been 40 individuals in 24 unrelated families from different ethnic backgrounds, due to 16 distinct variants identified by whole exome sequencing. We report two individuals from two unrelated families who presented with hypomyelination, spastic quadriplegia, nystagmus, and global developmental delay. Using clinical whole exome sequencing, we identified a newly reported, pathogenic, nonsense variant in case 1 (c.475C>T (p.Gln159Ter)), and a novel frameshift variant (c.234delG (p.Leu79CysfsX109)) in case 2. The clinical phenotype and the neuroimaging were similar in both patients and consistent with the neonatal onset form. The phenotypic overlap with other CNS hypomyelinating disorders, the intrafamilial and interfamilial variability and the non-diagnostic initial genetic and metabolic work up add significant diagnostic challenge. We thus, recommend comprehensive molecular testing by whole exome/genome sequencing as the initial test for patients presentingwith early onset nystagmus, hypotonia, rapidly progressive spastic quadriplegia, bilateral optic nerve atrophy, and diffuse hypomyelination.